Trichosporon asahii is the major etiologic agent of invasive trichosporonosis, an emerging worldwide deep-seated infection affecting mainly immunocompromised individuals. However, many aspects of the host immune response as well as the molecular and cellular events contributing to the establishment of infection are largely unknown. The long pentraxin-3 (PTX3) is a soluble pattern recognition receptor and an essential component of the humoral arm of innate immunity. PTX3 plays a nonredundant role in resistance against selected microbial pathogens, such as A. fumigatus, acting as an opsonin to facilitate phagocytosis and fungal clearance. Therefore, our aim was to characterize the role of this molecule in in vitro and in vivo models of infection by T. asahii. We show that infected human macrophages display an increased expression of PTX3, and that T. asahii uptake was enhanced by the opsonizing activity of PTX3. In an in vivo model of infection, Ptx3-deficient mice displayed increased fungal burden and tissue inflammatory pathology, when compared to the wild type counterpart. Finally, upon assessing the contribution of genetic variants in the PTX3 gene, known to underlie decreased expression of the protein, we disclosed a significant impairment in phagocytosis of T. asahii and cytokine production by human macrophages. Collectively, our results highlight a pivotal role of PTX3 in the immune response to T. asahii and suggest PTX3 deficiency as a major pathogenetic mechanism underlying susceptibility to trichosporonosis.